The evolution of cancer is tightly regulated by repeated cycles of cell proliferation, selection of the fittest clone and cell death of all weaker clones. Thereby, cancers strictly follow the rule of “Darwinian” selection throughout their existence. Although the induction of cell death in a cancer cell is wanted from a therapeutic viewpoint, it is also the driver behind selection for the most aggressive cancer cell clone. Therefore, it is our mission to provide insights into selective mechanisms at work during early cancer evolution in order to turn selection into efficient eradication of tumors.

Our research: In order to maintain healthy tissue homeostasis, normal cells must proliferate if needed but also die when asked. Typically, during aging, this process is slowed down, but individual cells have had a lifetime to accumulate faulty DNA, increasing their risk to become malignant. Malignant cancer cells within a tumor go on to evolve to avoid healthy tissue regulation resulting in constantly proliferating cancer cells with acquired cell death resistance. To achieve these cancerous hallmark features, early premalignant lesions likely undergo many cycles of fractional killing of premalignant cells which inevitably will select for the most resistant subclones. Thereby, unintentionally anti-cancer immune cells might contribute to the selection of the most aggressive cellular clone by creating constant selective pressure through cell death induction. To kill tumor cells, immune effector cells can make use of tumor necrosis factor (TNF) superfamily ligands such as TNF, CD95L, and TNF-related apoptosis-inducing ligand (TRAIL). Binding of these ligands to their cognate receptors expressed on tumor cells can trigger regulated types of cell death. In addition to direct ligand/receptor interaction-triggered regulated cell death such as extrinsic apoptosis and necroptosis, cancer cells can also undergo selective pressure from oxidative damage-associated regulated cell death such as ferroptosis, evasion of which is desirable for in lung cancers. To identify actionable vulnerabilities in these selection processes, the von Karstedt lab investigates the function of different modes of cell death in a) the selection of the fittest mutant KRAS clone in non-small cell lung cancer (NSCLC) and early pancreatic cancer formation, and b) by comparing these selection mechanisms with non-KRAS-mutated small cell lung cancer (SCLC).

Our successes: Silvia von Karstedt has previously identified a tumor- and metastasis-promoting role for cancer cell-expressed TRAIL-R2 in KRAS-driven pancreatic and lung cancer. Moreover, she has found that the same receptor/ligand system triggers the secretion of chemo- and cytokines, attracting and polarizing a tumor-supportive immune-environment supporting lung cancer growth. These findings have significantly advanced our understanding of the biology of death receptor function and biology beyond cell death induction in cancer and provide novel opportunities for therapeutic intervention.

Our goals: By unraveling mechanisms of selection-of-the-fittest in lung and pancreatic cancer, we anticipate to identify pathways which select for (NSCLC, pancreatic cancer) or against (SCLC) driver mutations, and at the same time to find new therapeutic vulnerabilities to treat these cancers. These insights will be vital for the development of novel therapeutic strategies targeting these mechanisms.

Our methods/techniques: The von Karstedt lab combines the use of genetically engineered and cigarette smoke-associated carcinogen-induced mouse models to explore the role of cell death-mediated selection during early tumor development. These approaches are underpinned by cell biological and biochemical studies on mechanistic aspects in cell culture.